Chronic caffeine exposure potentiates nicotine self-administration in rats

The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150–180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking. Received: 11 November 1997/Final version: 28 September 1998     

Modulation of nicotine-induced analgesia by calcium agonist and antagonist in adult rats

The involvement of calcium in nicotine-induced analgesia in male rats was explored using the tail-flick test. A single dose of nicotine (1 mg/kg SC) produced a maximal effect on tail-flick latency (15 s) within 8–10 min, which lasted for 4 min. Pretreatment with the calcium chelator, EDTA (250 µM/kg SC four injections at 15 min intervals), before the single dose of nicotine accelerated the onset and prolonged the duration of the nicotine-induced analgesia. The maximal effect on tail-flick latency occurred within 2 min and lasted for 10–20 min. Conversely, pretreatment with calcium chloride (1.5 mM/kg IP) attenuated nicotine-induced analgesia. It is suggested that nicotine may exert its antinociceptive effects via modulation of calcium fluxes across the neural membrane.Presented in part, as a poster at the 75th Annual Meeting of FASEB, Atlanta, Georgia, April 21–25, 1991.     

Effects of repeated withdrawal episodes,nicotine dose,and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats

Rationale The aversive aspects of nicotine withdrawal contribute to high relapse rates to tobacco smoking after cessation attempts. Objectives To investigate the influence of nicotine dose, duration of nicotine exposure, and withdrawal history on the severity of nicotine withdrawal in rats, as assessed by brain stimulation reward thresholds and somatic signs of withdrawal. Methods Repeated spontaneous and precipitated withdrawals were investigated through four successive removals of osmotic minipumps delivering nicotine/saline, or with daily injections of the nicotinic receptor antagonist dihydro-β-erythroidine during chronic nicotine/saline exposure, respectively. The effects of dose and duration of exposure were investigated using minipumps of varying duration delivering different nicotine doses. Results Increased duration of nicotine exposure: a) prolonged the duration but did not alter the magnitude of withdrawal-associated threshold elevations; b) increased somatic signs early during withdrawal. Increased total nicotine exposure (i.e. increased dose and exposure duration) increased the duration of threshold elevations (no effect on magnitude) but had no effect on somatic signs. Neither repeated spontaneous nor repeated precipitated withdrawals altered the magnitude of withdrawal significantly. Conclusions Increases in total nicotine dose resulted in increased severity of the affective aspects of withdrawal. Further, continuous drug exposure resulted in longer lasting withdrawal than intermittent administration even when the total nicotine dose was the same. There was no correlation between threshold elevations and somatic signs of withdrawal. In conclusion, the severity of nicotine withdrawal is mitigated by characteristics of the drug exposure regimen such as drug dose, duration of exposure and whether exposure is continuous or intermittent.     

Prenatal nicotine exposure increased susceptibility to electroconvulsive shock (ECS) in adult rats

Female rats were treated during pregnancy (days 1-20) with nicotine (1 mg/kg SC, b.i.d.). When some aspects of maternal behavior and developmental parameters were recorded in mothers and pups, respectively, no changes were detected in the experimental group as compared with controls. However, adult offspring of nicotine-treated rats showed an increased susceptibility to ECS. These results demonstrate long-lasting deleterious effects induced by nicotine exposure during fetal life.     

Adolescent exposure to nicotine results in reinforcement enhancement but does not affect adult responding in rats

Background

Adolescence is a period of development associated with a peak in an organism's responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether (1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and (2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood.

Methods

Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (postnatal day 29–42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules.

Results

Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.

Conclusions

Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.     

Differential behavioral effects of nicotine exposure in adolescent and adult rats

Rationale Although the detrimental effects of nicotine in early brain development and the addictive properties in adulthood are well known, little is known about the neurobiological effects of nicotine in adolescence. An important question is whether adolescents and adults differ in the development of nicotine sensitization and drug-cue conditioning.Objective To examine the behavioral effects of multiple, repeated injections of nicotine on both sensitization and drug-cue conditioning in the adolescent rat, and to compare this profile with the adult rat.Methods Sixteen male adolescent (28 day) and 16 young adult (70 day) rats were given injections of either saline or nicotine and tested for motor activity for 90 min for ten consecutive days. Following 4 days of no testing, animals were given a sham injection and placed in the testing apparatus for 90 min. A dose–response curve for nicotine was also generated using two additional groups of ten adolescent and ten adult male rats.Results Adolescent rats, unlike adults, did not exhibit signs of nicotine-cue conditioning, and displayed less robust sensitization to the locomotor effects of nicotine than adults. Dose–response testing revealed differences in adolescent responsivity to nicotine in measures of rearing, but not ambulation. Initial exposure to nicotine resulted in increased sensitivity to the motor-activating effects of nicotine but less sensitivity to the depressant effects of nicotine in rearing in adolescents.Conclusions Adolescent animals display different long-term neuroadaptive responses to nicotine than adult animals, possibly related to immature or still-developing plasticity mechanisms in the prefrontal cortex.Electronic Supplementary Material Supplementary material is available for this article at .     

Caffeine potentiates the discriminative-stimulus effects of nicotine in rats

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.     

Sex-dependent biological changes following prenatal nicotine exposure in the rat

Nicotine was administered to adult female rats in drinking water starting 6 weeks before mating and continuing throughout pregnancy. The litters were cross-fostered to control dams at birth. Prenatal nicotine treatment reduced both the number of male rats born and the male birth weight. Female offspring were not significantly affected. Rearing activity was reduced in male but not female offspring either when tested over a 24 hour period in a home cage environment or during a 10 minute exposure in an open field. Horizontal locomotor activity was reduced only during the first 5 minutes in the open field and again the effect was found only in the males. Baseline plasma corticosterone levels were reduced in both male and female offspring but there was no effect on stress-elevated corticosterone levels.     

Dose, duration and pattern of nicotine administration as determinants of behavioral dependence in rats

Rationale Relatively little is known about the role of dose, duration, and pattern of nicotine exposure in the development of dependence. Disruption of learned behavior during antagonist-precipitated withdrawal can be a sensitive, quantitative measure of behavioral dependence. Objectives The present study sought to determine whether behavioral dependence upon nicotine could be induced in rats and, if so, what exposure conditions were essential for inducing it. Our primary focus was on whether continuous exposure over several days was necessary to produce dependence. Methods Male Sprague–Dawley rats were trained to lever press under fixed-ratio 10 schedules of food reinforcement during daily, 15-min experimental sessions. Nicotine was then administered s.c. via osmotic minipumps that delivered various nicotine dosage regimens, some including 24-h nicotine-free periods, to manipulate pattern of exposure. The presence of dependence was tested with challenges with the nicotinic acetylcholine receptor antagonist, mecamylamine, or during spontaneous withdrawal. Results After 7 days of 3, 6, and 12 mg kg⁻¹ day⁻¹ nicotine administration, response rates were significantly reduced in nicotinized, but not in saline-treated rats following mecamylamine challenges. Subsequent studies demonstrated that 4 days, but not 3 days, of cumulative 3 mg kg⁻¹ day⁻¹ nicotine administration was sufficient to induce dependence. The induction of dependence could be prevented by imposing a nicotine-free period between the first and second days during these 4-day regimens but not at other times. Conclusion Behavioral dependence upon nicotine can be induced in the rat, and its induction is dependent upon its cumulative duration and pattern of exposure suggesting that tobacco dependencies could be controlled by similar determinants.     

mGlu1 receptor blockade attenuates cue- and nicotine-induced reinstatement of extinguished nicotine self-administration behavior in rats

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.     

Investigating the actions of bupropion on dependence-related effects of nicotine in rats

Abstract Rationale. The clinical success of the antidepressant bupropion, marketed as Zyban in smoking cessation, presents an ideal opportunity to unravel its mechanism of action utilising animal models of nicotine dependence. Objective. The present experiments utilise bupropion as a reference compound to examine putative interactions with stimulus properties of nicotine in rats. Methods and results. In male hooded Lister rats, bupropion (10 and 30 mg/kg IP) administered 30 min prior to each intravenous nicotine (0.03 mg/kg per infusion) self-administration session failed to attenuate rates of nicotine intake. Moreover, following the large dose of bupropion, nicotine intake was enhanced and response rates remained elevated throughout the 28-day course of treatment. To examine interactions with subjective effects of nicotine, rats trained to discriminate nicotine (0.2 mg/kg SC) from vehicle were tested with bupropion (1, 3, 10 and 30 mg/kg IP). Bupropion pre-treatment failed to exert a "nicotine-like" action and also failed to attenuate the orderly dose-related discrimination function of nicotine (0.05–0.4 mg/kg SC) in rats. Using the conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake, bupropion (3, 10 and 30 mg/kg IP) pre-treatment failed to modify the aversive effects produced by a threshold dose of nicotine (0.2 mg/kg SC). Conclusions. The results obtained with bupropion in these animal models of dependence suggest this antidepressant may not directly interact with stimulus properties of nicotine; rather its clinical efficacy may be exposed in animal models that are based upon chronic exposure to nicotine and upon abstinence effects. Electronic Publication     

Prenatal toxicity of acyclovir in rats

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crownrump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 M). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (± SD) of 60.3±14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6±16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.     

18-Methoxycoronardine attenuates nicotine-induced dopamine release and nicotine preferences in rats

Two studies were conducted to assess, in vivo, potential anti-nicotinic effects of the iboga alkaloid ibogaine and its synthetic congener 18-methoxycoronaridine (18-MC). As previously demonstrated for ibogaine, using microdialysis, pretreatment (19 h beforehand) with 18-MC (40 mg/kg, IP) significantly attenuated nicotine-induced dopamine release in the nucleus accumbens of awake and freely moving rats. In an oral model of nicotine self-administration, both ibogaine and 18-MC decreased rats’ preferences for nicotine for at least 24 h. Acutely, during the first hour after administration, ibogaine depressed responding for water as well as for nicotine; however, during this same time, 18-MC reduced nicotine intake without affecting responding for water. The results suggest that 18-MC might be the prototype of a new treatment for smoking. Received: 26 November 1997/Final version: 17 February 1998     

Repeated nicotine exposure enhances responding with conditioned reinforcement

Rationale Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes.Objective This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion.Methods Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 µg per side) prior to the conditioned reinforcement test.Results Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine.Conclusions These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.     

Analgesia induced by chronic nicotine infusion in rats: differences by gender and pain test

RATIONALE: Acute administration of nicotine induces analgesia with subsequent development of tolerance. In human studies, females are less sensitive to the analgesic effects of nicotine than males. Few previous animal studies have investigated analgesic effects of chronic nicotine administration or addressed gender differences. OBJECTIVES: To investigate whether chronic administration of nicotine induces analgesia in male and female rats as assessed by a battery of standard pain assays, if tolerance develops, and if hyperalgesia occurs following cessation of nicotine. METHODS: Nicotine (free base; 6 mg/kg/day i.v.) or saline was administered for 2 weeks via implanted osmotic pumps. Pain behavior was assessed before, during, and for 3 weeks after nicotine infusion by measuring tail flick latency, hot-plate latency, and thermal paw withdrawal latency. The paw-withdrawal threshold to non-noxious mechanical stimuli was also measured. Effects of nicotine infusion, gender, and time were assessed by three-way analyses of variance. RESULTS: Both male and female rats exhibited a comparable degree of analgesia in the hot-plate test with development of tolerance during the 2-week infusion period. Males, but not females, showed analgesia in the tail flick test. Analgesia was not observed for thermally evoked paw withdrawal in either males or females, nor did nicotine affect non-noxious mechanically evoked paw withdrawals. Males and females showed cessation of weight gain during the first week of nicotine infusion. CONCLUSIONS: Chronic nicotine-induced analgesia was confirmed in both male and female rats as assessed using the hot-plate test which reflects integrated pain behavior. Males, but not females, exhibited analgesia in a nociceptive withdrawal reflex test (tail flick), indicating that nicotine-induced analgesia may depend on both the type of pain test and gender. The lack of nicotine-induced analgesia assessed by the tail flick reflex test in female rats is consistent with recent human studies showing that nicotine reduces pain elicited by brief noxious cutaneous stimulation in male but not female subjects.     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

Neonatal ethanol exposure produces a hyperalgesia that extends into adolescence,and is associated with increased analgesic and rewarding properties of nicotine in rats

Rationale Drug exposure during CNS development may alter subsequent dependence liability. We postulated that early alcohol exposure might produce persistent alterations in responses to noxious stimuli. Because relief of physical discomfort may be negatively reinforcing, changes in responses to noxious stimuli produced by early alcohol exposure may increase the rewarding properties of nicotine, a potent analgesic. Such factors may contribute to the high level of alcohol and nicotine co-abuse in humans.Objectives The purpose of this study was to determine whether neonatal ethanol exposure in rats altered responses to noxious stimuli, and whether nicotine would then be more rewarding to the alcohol-exposed offspring, perhaps via its analgesic actions.Methods Neonatal rats received ethanol by gavage (5.0 or 6.5 g/kg) on postnatal days (PND) 9–13. An iso-caloric control group was also included. Rats were then tested to assess responsiveness to a mild noxious heat stimulus, as measured in the tail-flick assay (PND 14 and PND 28), for their response to acute analgesic injections of either nicotine or ethanol (PND 28), and for nicotine induced conditioned place preference (CPP) (PND 36).Results Neonatal ethanol exposure produced hyperalgesia during the first 24 h after alcohol withdrawal (PND 14) that continued through PND 28. The analgesic effects of 12.5 g/kg nicotine were enhanced approximately 2-fold in adolescent rats with previous ethanol histories, relative to controls. These ethanol-exposed rats also showed a significant CPP to nicotine, whereas controls showed no CPP.Conclusions Persistent decreases in tail-flick response latencies suggestive of hyperalgesia were observed following neonatal ethanol exposure in the rat. These changes were accompanied by increases in the analgesic and place-conditioning effects of nicotine in adolescence. If similar effects occur in humans, prenatal alcohol exposure may play a role in an increased risk for the rewarding effects and dependence liability of nicotine later in life.     

Prenatal cocaine and/or nicotine exposure in rats: Preliminary findings on long-term cognitive outcome and genital development at birth

Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8–20); nicotine (4 mg/kg/day continuous SC infusion on GD 4–20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the β-noradrenergic antagonist propranolol (10–20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13–42% and offspring birth weight was reduced by 7–12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1–5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.     

Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

Rationale  The ability of tobacco harm reduction strategies to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon and assessing the feasibility of harm reduction interventions. Objective  The objective of the study was to use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Methods  Rats were trained for NSA during daily 23-h sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Results  Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23-h sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. Conclusions  These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans.     

Environmental stimuli promote the acquisition of nicotine self-administration in rats

RATIONALE: Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. OBJECTIVES: In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. METHODS: Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. RESULTS: Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. CONCLUSIONS: These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.